The overall goal of the Signal Transduction Program (STP) is to elucidate the mechanisms that govern activation and repression of signaling cascades during normal development, neoplastic transformation and tumor progression. This goal is based on the premise that abnormalities in signal transduction are universal features of human cancer cells, and underiie virtually all aspects of the transformed phenotype. Members of the Signal Transduction Program currently pursue three major investigative areas: (1) kinases and phosphatases that are important in tumor development and known to undergo changes in human tumors; (2) ubiquitin ligases and ubiquitin-like proteins that play important roles in cellular pathways that are deregulated during tumor development and progression; and (3) an emerging theme of altered metabolic signaling in cancer. The Signal Transduction Program was established in 2001, and has been greatly strengthened since the last renewal by recruitment of new faculty members with expertise that complements the interests of the original faculty members. Of the 16 current members, 11 members have been recruited since 2003. Among them is Dr. Ze'ev Ronai, who was recruited as new Program Leader for the Signal Transduction Program in 2004. The Program is highly collaborative and interactive as evidenced by joint laboratory meetings, joint mentoring of graduate students and postdoctoral fellows, joint mentoring program for young faculty, monthly postdoctoral fellow presentations, monthly faculty meetings, monthly interest group (ubiquitin, ER stress) meetings, the annual postdoctoral retreat, and several Program Project grant initiatives underway. As a result of these activities, Program members lead or participate in 4 POl grants (2 from NCI), in multiple shared federal and state grants, and multiple co-authored publications. The high productivity of the Program during the past grant period is further documented by 21 ROI grants (7 from NCI) held by the Program members; by the current total annual grant funding of $14.5MM ($8.2MM direct); by 392 publications since last review, and by 65 Program publications in 2008, which represent 11% of intra- and 31% of interprogrammatic collaborations, respectively.